The candidate for this proposal, Dr. Kudej, has completed a small animal surgery residency and PhD program in biomedical engineering and received his postdoctoral training in cardiovascular physiology at Harvard Medical School. His goal is to further establish himself as a cardiovascular researcher and to acquire additional basic science research tools to allow him to develop an independent R01 proposal and build a successful and rewarding career in cardiovascular research. The current proposal is designed first to examine the mechanisms responsible for the maintenance of myocardial blood flow present in two models of hibernating myocardium: a swine model of chronic coronary constriction, which demonstrates many characteristics of hibernating myocardium in humans, and during true hibernation in the woodchuck (M. monax). Second, the mechanisms governing the alterations in regional myocardial function in these two models will be examined. Specifically, the two hypotheses of this proposal are: A) Coronary blood flow is maintained in hibernating myocardium, potentially due to up-regulation of NO; and B) Adaptive alterations in systolic and diastolic left ventricular function present distal to the ameroid coronary constrictor in swine and in hibernating woodchuck hearts are associated with a coordinated modification of calcium handling mechanisms. The information to be acquired from this proposal will be directly applicable to humans with coronary artery disease and chronic coronary stenosis. Additionally, understanding the basic mechanisms underlying the enhanced performance of myocardial tissue from hibernating mammals may provide insights into human pathology. In July 1999, the PSUCM will established a Department of Integrative Molecular Medicine and Genetics, to be overseen by Stephen Vatner, MD, a well-known researcher who was recruited from Harvard University. Dr. Vatner's investigative team has grown rapidly and faculty who have joined the department will play an important role in training Dr. Kudej. The department is well supported externally. NIH funding for institute faculty includes one program project award, one merit award, and several R01s, R29s, and National Research Service Awards.